Alessandro Riva, MD
Treatment with ofatumumab (Arzerra) plus fludarabine and cyclophosphamide significantly improved progression-free survival (PFS) compared with fludarabine and cyclophosphamide alone in patients with relapsed chronic lymphocytic leukemia (CLL), according to topline findings from the phase III COMPLEMENT 2 study.
Results from the study were released by Novartis, which acquired the drug from GlaxoSmithKline in early March 2015 as part of a multi-billion-dollar product exchange. Novartis is analyzing data from the study, with plans to submit the results to regulatory agencies.
"Patients eventually stop responding to current CLL treatments, making the investigation of new options critically important," Alessandro Riva, MD, global head, Novartis Oncology Development and Medical Affairs, said in a statement. "We're encouraged by these positive topline results from COMPLEMENT 2, which demonstrate continued momentum for our expanding oncology portfolio, and we look forward to sharing the full results of this study at an upcoming medical meeting."
In the study, 365 patients were randomized to receive ofatumumab plus fludarabine and cyclophosphamide or the chemotherapy alone. Ofatumumab was administered at 300 mg on day 1 of the first cycle followed by 1000 mg on day 8. For subsequent cycles, the drug was administered at 1000 mg on day 1.
The primary endpoint of the study was PFS. Secondary outcome measures focused on overall survival, response, and patient reported outcomes. While data from the study were not released, the company noted that the P
value for the improvement seen in PFS was .0036. Additionally, there were not any unexpected adverse events experienced with ofatumumab in the study.
A preceding phase II study looking at ofatumumab in combination with fludarabine and cyclophosphamide demonstrated an overall response rate (ORR) of more than 70% in untreated patients with CLL. This study examined ofatumumab at 500 mg (n = 31) and 1000 mg (n = 30).
Patients in the 500 mg arm experienced an ORR of 77% and those in the 1000 mg arm had an ORR of 73%. The complete response rate with the smaller dose was 32% compared with 50% with the larger dose.
For patients treated with the 1000 mg dose, the most common grade 3/4 adverse events were infections (23%), neutropenia (60%), thrombocytopenia (23%), anemia (20%), and hemolytic anemia (10%). Overall, 10% of patients developed febrile neutropenia.
In April 2014, the FDA approved ofatumumab plus chlorambucil for previously untreated patients with CLL who were considered inappropriate for treatment with fludarabine, based on an improvement in progression-free survival (PFS) in the phase III COMPLEMENT 1 trial.
In the study, patients were randomized in a 1:1 ratio to receive ofatumumab plus chlorambucil (n = 221) or chlorambucil alone (n = 226). In the ofatumumab arm, 82% of patients received more than 6 cycles of therapy.
Median PFS by independent review was 22.4 months with ofatumumab plus chlorambucil compared with 13.1 months for chlorambucil alone (HR = 0.57; 95% CI, 0.45-0.73; P
< .001). ORR was 82% versus 69% with a complete response rate of 12% versus 1%, for ofatumumab plus chlorambucil compared with chlorambucil alone, respectively.
The most common grade 3/4 adverse event in this study was neutropenia, which occurred in 26% of patients treated with ofatumumab compared with 14% for chlorambucil alone. Infections rates were similar, at 15% and 14%, for ofatumumab plus chlorambucil versus chlorambucil alone.
Ofatumumab targets CD20 on the surface of both normal and malignant B-cells, which induces cell death through antibody-dependent cell-mediated toxicity, complement-dependent cytotoxicity, and apoptosis. The FDA first approved the agent in October 2009, as a treatment for patients with CLL who no longer respond to chemotherapy.
The drug was co-developed by Genmab and GSK, through an agreement signed in 2006. However, under the March 2015 transaction, Genmab removed itself from all funding liabilities for ofatumumab. Novartis will continue to development and commercialization the drug for cancer-related indications, while GSK will explore ofatumumab in autoimmune diseases.
“We are pleased with the positive topline results in this pivotal study of ofatumumab in combination with fludarabine and cyclophosphamide in relapsed CLL. This outcome is good news for patients with CLL, a disease for which relapses are inevitable," Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement. "We look forward to sharing additional data from the study at an upcoming medical conference and to discussions with the regulatory authorities in collaboration with Novartis."